Human glutathione S-transferase deficiency as a marker of susceptibility to epoxide-induced cytogenetic damage.
The identification of genetic traits that predispose individuals to environmentally induced cancers is one of the most important problems in cancer risk assessment. Genetic deficiency in the mu-isozyme of the glutathione (GSH) S-transferases (EC 2.5.1.18) has recently been associated with increased lung cancer risk. To test whether this association could arise from a metabolically mediated sensitivity to mutagenic substrates, cytogenetic damage in lymphocytes from 21 isozyme-deficient and 24 nondeficient individuals was induced. Cells were treated with trans-stilbene oxide, an excellent substrate for GSH S-transferase mu, or cis-stilbene oxide, a poor substrate for the isozyme. Sister chromatid exchange induction was measured as an indicator of cytogenetic damage. A trimodal distribution of trans-stilbene oxide-induced sister chromatid exchanges was observed in the population, including resistant, moderate, and highly sensitive groups. Glutathione S-transferase mu deficiency was associated with both moderate and high sensitivity to trans-stilbene oxide-induced damage but had no effect on cis-stilbene oxide-induced sister chromatid exchange. The results indicate that GSH S-transferase mu, a proposed marker of cancer susceptibility, is also a marker of susceptibility to the induction of cytogenetic damage by a certain class of mutagens. The differential effects of the cis- and trans-isomers of stilbene oxide illustrate that the stereoselectivity of GSH S-transferase mu toward various alkene epoxide substrates can be an important factor affecting individual sensitivity to DNA-damaging epoxides.
Wiencke
J K
JK
Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco 94143.
Kelsey
K T
KT
Lamela
R A
RA
Toscano
W A
WA
D000328:Adult; D000368:Aged; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D005982:Glutathione Transferase / Q000172:deficiency*; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency*; D008214:Lymphocytes / Q000166:cytology / Q000201:enzymology*; D008297:Male; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013267:Stilbenes / Q000009:adverse effects*
D007527:Isoenzymes; D013267:Stilbenes; D005982:Glutathione Transferase; C025906:stilbene oxide